title: Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice.
abstract: We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91(phox) or p47(phox) exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.
authors.affiliation: Division of Nephrology, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA. zhaihua@njmu.edu.cn
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.forename: Ningning
authors.initials: N
authors.lastname: Wang
authors.forename: Tyson J
authors.initials: TJ
authors.lastname: Tidwell
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000633:toxicity; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000652:urine; D018384:Oxidative Stress / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology / Q000633:toxicity; D012965:Sodium Chloride / Q000008:administration & dosage
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D009589:Nitrogen Oxides; D012402:Rotenone; C075750:8-epi-prostaglandin F2alpha; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D000450:Aldosterone; C056165:acetovanillone; D015237:Dinoprost; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1